Antipsychotic Effects of Ethanol Leaf Extract and Fractions of Milicia Excelsa (Moraceae) in Mice

Journal of Pharmaceutical Research International

22(6): 1-10, 2018; Article no.JPRI.42383 ISSN: 2456-9119 (Past name: British Journal of Pharmaceutical Research, Past ISSN: 2231-2919, NLM ID: 101631759)

Antipsychotic Effects of Ethanol Leaf Extract and Fractions of Milicia excelsa (Moraceae) in Mice

Lateef Abiola Akinpelu1,2*, Moses Atanda Akanmu2 and Efere Martins Obuotor3

1Department of Pharmacology and Toxicology, College of Pharmacy, Igbinedion University, Okada, Edo State, Nigeria. 2Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria. 3Department of Biochemistry, Faculty of Science, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria.

Authors’ contributions

This work was carried out in collaboration between all authors. Author LAA managed the experimental process, performed the statistical analysis of the study, managed the literature searches and wrote the first and final version of the manuscript. Author MAA designed the study, managed the experimental process and managed the analyses of the study. Author EMO designed the study, managed the experimental process and managed the analyses of the study. All authors read and approved the final manuscript.

Article Information

DOI: 10.9734/JPRI/2018/42383 Editor(s): (1) Dr. Nawal Kishore Dubey, Professor, Centre for Advanced Studies in Botany, Banaras Hindu University, India. Reviewers: (1) Dario Siniscalco, University of Campania, Italy. (2) Ioana Stanciu, University of Bucharest, Romania. (3) Barış Önen Ünsalver, Ünsalver Uskudar University, Turkey. Complete Peer review History: http://www.sciencedomain.org/review-history/25328

Received 13th April 2018 th Original Research Article Accepted 19 June 2018 Published 29th June 2018

ABSTRACT

Aim: This study investigated the acute toxicity (LD50) and antipsychotic potentials of ethanol leaf extract of Milicia excelsa (EME), hexane (HF), ethyl acetate (EAF), butanol (BF) and aqueous (AF) fractions in mice. Study Design: This study used experimental mice models predictive of human psychosis. Place and Duration of Study: Department of Pharmacology, Faculty of Pharmacy, Obafemi Awolowo University, Ile-Ife, Osun State, Nigeria, between January 2014 to February 2015. Methodology: The antipsychotic effect was assessed using swim-induced grooming; apomorphine-induced climbing and ketamine-induced hyperlocomotion behaviours in mice.

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*Corresponding author: E-mail: [email protected];

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Results: The results showed that the LD50 of the ethanol extract and its various fractions were greater than 5000 mg/kg. EME and all its fractions significantly (P < 0.05) decreased the number of grooming while the duration of grooming was significantly (P < 0.05) reduced by EME, EAF and AF in swim-induced grooming. EME and EAF significantly (P < 0.05) inhibited climbing behaviour in apomorphine-induced climbing. EME and all the fractions significantly (P < 0.05) inhibited the hypermotility induced by ketamine while the number of ataxia was significantly (P < 0.05) reduced by EME, EAF and AF in ketamine-induced hyperlocomotion, with AF producing a stronger ataxia reducing effect compared to haloperidol, a reference antipsychotic drug. EME and EAF showed consistent antipsychotic activities in all the models used. Conclusion: This study concludes that EME and all its fractions may be safe and contain antipsychotic principles, thus, providing scientific evidence for the suggested ethnomedicinal use of the leaf in treating insanity in traditional medicine.

Keywords: Milicia excelsa; antipsychotic; swim-induced grooming; apomorphine; ketamine.

1. INTRODUCTION has been reported to have wound healing effects [18], while the anti-inflammatory effect of the Schizophrenia is a devastating psychiatric stem bark has also been reported [19]. disorder that disrupts cognition, emotion, language, and thought. It affects 0.5%–1.5% of This study was therefore designed, to provide the population [1]. Abnormality in scientific evidence, for the traditional claim of the neurotransmitters pathways such as hyperactivity leaf in the treatment of insanity [14], coupled with of dopaminergic system [2], hypofunction of its widespread use among the Yoruba speaking glutaminergic pathway via the NMDA receptor [3] tribe of South Western Nigeria as an and the serotoninergic system, [4] have been antipsychotic herbal drug (Personal communica- implicated in the brain of individuals with tion). To the best of our knowledge; the schizophrenia. antipsychotic effect of the leaf has not been reported upon comprehensive literature search. The poor efficacy and tolerability of the currently available antipsychotic drugs have limited their 2. MATERIALS AND METHODS use. Due to rise in psychiatric disorders and adverse effects associated with the existing 2.1 Plant Identification and Authentica- therapy; it becomes pertinent and imperative for tion clinicians to search for alternative remedies for the treatments of this neurobehavioural disorder Milicia excelsa leaves were collected within the [5]. campus of the Obafemi Awolowo University (OAU) Ile Ife Nigeria. It was identified and Medicinal plants play an essential role in health authenticated by Mr. G. A. Ademoriyo of the care delivery and needs of rural populace in Herbarium Unit, Department of Botany, Faculty Africa, and among other underdeveloped or third of Sciences, OAU, Ile-Ife and herbarium number world countries. Especially in the treatment of Ife-17482 was obtained. diseases, [6] and also in developed countries, [7] because they are considered more natural, safer, 2.2 Preparation of Plant Materials and affordable compared to “manufactured” pharmaceutical products [8,9]. The leaves of Milicia excelsa were air dried at room temperature. The dried leaves were Milicia excelsa (welw.) C.C. Berg belongs to the pulverized and 1.0 kg of the powder was family of Moraceae, popularly known as Iroko extracted with 3 liters of ethanol (70%) for 72 h. tree or African teak. It is a large deciduous tree The marc was re-extracted once and the 30 to 50 m high occurring naturally in humid combined extract was concentrated in vacuo at a forests of West Africa [10]. Its latex, leaf, stem temperature of 40ºC to yield 70 g (7.0%) crude bark, root, fruit, and ashes are used in African extract and coded (EME). Sixty gram (60 g) of traditional medicines to prepare traditional the crude extract was successively partitioned remedies for the treatment of malaria [11], into n-hexane (HF), ethyl acetate (EAF), n- rheumatism [12], sexual dysfunction [13], mental butanol (BF) and aqueous (AF) fractions. The illnesses [14,15,16], anaemia, [17] among other fractions were again concentrated in vacuo diverse folkloric uses. Pharmacologically, the leaf to give n-hexane, ethyl-acetate, n-

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butanol and aqueous fractions (Personal p.o of the extract and fraction(s), Group V communication). (Reference drug). Male mice were used for this study because of the psychoprotective effect 2.3 Drugs of oestrogen and progesterone in females [22,23,24,25]. Haloperidol, Apomorphine, Tween 20 (Sigma Chemicals Co, St. Louis, Missouri, U.S.A.), 2.6.1 Swim induced grooming (SIG) Ketamine hydrochloride (Rotexmedica, Germany) and physiological saline (Unique Grooming behaviour was induced in mice by a Pharmaceutical Limited, Lagos, Nigeria). EME short period of swimming as previously described and fractions were dissolved with 2% Tween 20 [26]. The control mice were pretreated with 2% and made up to the required volume with normal Tween 20 in normal saline (10 mL/kg, p.o.), EME saline. The drugs, crude extract and fractions (250, 500 and 1000 mg/kg, p.o.). One hour post were freshly prepared on each day of the treatments, mice were individually placed in a experiments. swimming cylinder (8 x 8 x 18 cm high) filled with fresh water maintained at 32°C and allowed to 2.4 Laboratory Animals swim for three minutes. The reference, haloperidol (D2 receptor antagonist) treated Adult male albino mice (18–25 g) were obtained positive control group received a dose (1 mg/kg, from the Animal House, Department of i.p.), 30 minutes before being subjected to Pharmacology, Faculty of Pharmacy, OAU, Ile- swimming for three minutes. After an expiration Ife. The animals were acclimatized for one week of 3 minutes swimming session, each mouse in a cage lined with wood shavings at room was then removed and dried with a towel for 30 temperature, under 12 h of light/12 h of darkness seconds and placed immediately into single cycle. The animals were fed on standard animal Perspex boxes. The number and the total pellets and water ad libitum. Experimental duration of grooming episodes were recorded for protocols were carried out in accordance with the 15 minutes. The water in the cylinder was National Institute of Health [20]. The experiments changed after each mouse had swum. The were carried out between 9.00 am and 3.00 pm procedures were repeated using HF (250-1000 on each day of the experiment. mg/kg, p.o.), EAF (250-1000 mg/kg, p.o.), BF (250-1000 mg/kg, p.o.) and AF (250-1000 mg/kg, 2.5 Acute Toxicity Study p.o.).

As a follow up to the preliminary acute toxicity 2.6.2 Ketamine-induced hyperlocomotion studies of EME and BF, which were determined using Lorke’s method (Personal communication), The exploratory activity of mice was assessed acute oral toxicity assessment of HF, EAF, and using open field test (OFT) as adapted from AF were also carried out using Lorke’s method earlier studies [27,28]. The control animals were [21]. The experiments were carried out in two treated with 2% Tween 20 in normal saline (10 phases. In the first phase, HF was administered mL/kg, p.o.), EME (250, 500 and 1000 mg/kg, via an orogastric route to three groups of mice p.o.). One hour after treatments, each mouse (n=3) at the doses of 10, 100 and 1000 mg/kg received ketamine (10 mg/kg i.p.) and was respectively. In the following phase, another immediately put in the open field, and observed three groups of mice (n=1) were again for the number of squares crossed (locomotor administered 1600, 2900 and 5000 mg/kg of HF activity) and ataxia (the frequency of staggered via an orogastric route. After oral ingestion of HF movements and number of falls) during three in each of the two phases, each mouse was minutes, after one minute for acclimatization. The observed for obvious toxic symptoms and positive control group received haloperidol (0.2 mortality for 24 h post administration. These mg/kg, i.p.) 30 min before ketamine (10 mg/kg, procedures were repeated for EAF and AF. i.p.). The procedures were repeated using HF (250-1000 mg/kg, p.o.), EAF (250-1000 mg/kg, 2.6 General Experimental Design p.o.), BF (250-1000 mg/kg, p.o.) and AF (250- 1000 mg/kg, p.o.). Male mice were randomly divided into 5 groups (n = 5). Group I (Vehicle), the animals in this 2.7 Statistical Analysis group received 2% Tween 20 in normal saline (10 mL/kg, p.o.), Group II-IV (Treatment groups), Results are expressed as mean ± S.E.M. The the animals received 250, 500 and 1000 mg/kg, significance of difference between groups were

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analysed using one way analysis of variance group. The standard drug haloperidol (ANOVA), followed by post hoc analysis using significantly (P < 0.05) reduced the number of the Student- Newman-keuls test. Non parametric climbing behaviour when compared to vehicle tests were analysed by Kruskal Wallis followed treated group (Fig. 2). by Dunn test using GraphPad InStat® Biostatistics software (GraphPad Software, Inc., 3.4 Effects of EME, HF, EAF, BF and AF La Jolla, USA). The level of significance for all on Ketamine-induced Hyperlocomo- tests was set at P < 0.05. tion in Mice

3. RESULTS Ketamine (Ket 10 mg/kg, i.p.) significantly (ǂP < 0.05) increased the number of locomotion while 3.1 The Results of Acute Toxicity Study the standard drug haloperidol significantly (P < 0.05) decreased the hyperlocomotion induced by The acute toxicity (LD50) of HF, EAF and AF ketamine when compared to the vehicle treated were greater than 5000 mg/kg, p.o. control group. The hyperlocomotion induced by

ketamine (10 mg/kg, i.p.) was significantly [F (4, 3.2 Effects of the EME, HF, EAF, BF and 25) = 56.658, P < 0.0001)], [F (4, 25) = 65.154, P AF on Swim-induced Grooming < 0.0001] and [F (4, 25) = 29.128, P < 0.0001] Behaviour in Mice reduced by the pretreatment with EME, EAF and AF respectively at all doses (250, 500 and 1000 The results obtained showed that EME, HF, mg/kg, p.o.) when compared to ketamine treated EAF, BF and AF at all the doses used (250, 500 group. and 1000 mg/kg, p.o.) significantly [F (4, 25) = 22.345, P < 0.0001)], [F (4, 25) = 22.876, P < HF at the doses of 250 and 1000 mg/kg, p.o 0.0001], [F (4, 25) = 36.101, P < 0.0001], [F (4, significantly [F (4, 25) = 52.436, P < 0.05] and BF 25) = 21.942, P < 0.0001] and [F (4, 25) = at the doses of 250 and 500 mg/kg, p.o. 39.899, P < 0.0001] respectively decreased the significantly [F (4, 25) = 52.309, P < 0.001] number of grooming activity compared to the decreased hyperlocomotion induced by ketamine vehicle treated control. The effect was most (10 mg/kg, i.p.) when compared to ketamine pronounced in AF in a dose-dependent manner, treated control group. EME, HF, EAF, BF and AF followed by EAF, HF with BF having the lowest produced significant (P < 0.05) increase in activity. However, EME, EAF and AF at all the locomotion when compared to the vehicle treated doses used (250, 500 and 1000 mg/kg, p.o.) group without ketamine administration (Fig. 3) significantly [F (4, 25) = 178.72, P < 0.0001)], [F (Panel A). (4, 25) = 93.227, P < 0.0001], and [F (4, 25) = 88.747, P < 0.0001] decreased the duration of 3.5 Effects of EME, HF, EAF, BF and AF grooming activity respectively compared to the on Ataxia in Ketamine-induced vehicle treated control group. This effect was Hyperlocomotion in Mice more pronounced in EAF than AF. BF and HF at all aathe doses used showed no significant effect Ketamine significantly (P < 0.05) increased the on duration of grooming when compared to the number of ataxia but standard drug haloperidol vehicle treated group. The standard drug, significantly (P < 0.05) decreased the number of haloperidol significantly (P < 0.05) decrease both ataxia when compared to the vehicle control the number and duration of behaviour (Fig. 1) group. The number of ataxia induced by (Panel A and B). ketamine was significantly [F (4, 25) = 30.046, P < 0.0001)], [F (4, 25) = 41.582, P < 0.0001)] and 3.3 Effects of EME, HF, EAF, BF and AF [F (4, 25) = 29.128, P < 0.0001)] decreased by on Apomorphine-induced Climbing pretreatment with EME, EAF and AF respectively Behaviour in Mice at all the doses used (250, 500 and 1000 mg/kg, p.o.) when compared to ketamine treated control The results obtained showed that EME and EAF group. HF and BF did not affect the number of at 1000 mg/kg and 250 mg/kg respectively ataxia behaviour. The results are presented in significantly (P < 0.05) attenuated the climbing Fig. 3 (Panel B). behaviour in apomorphine-induced climbing behaviour in mice when compared to the vehicle 4. DISCUSSION treated control group. However, HF, BF and AF did not significantly inhibit climbing behavior This study investigated the oral acute toxicity when compared to the vehicle treated control (LD50) of HF, EAF and AF while the antipsychotic

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effect of EME, HF, EAF, BF and AF were also EME and BF were greater than 5000 mg/kg investigated. The LD50 of HF, EAF, and AF were per body weight. EME and EAF showed found to be greater than 5000 mg/kg suggesting antipsychotic effects in all the models of swim- that the fractions may be safe in mice, since no induced grooming (SIG), apomorphine- acute toxicity may be considered above 5 g/kg induced climbing test (AIC) and ketamine- body weight [29]. Preliminary investigations from induced hyperlocomotion models (KIH) used in our laboratory have also shown that the LD50 of this study.

PANEL A

PANEL B

Fig. 1. Antipsychotic effect of EME, HF, EAF, BF and AF on the number of grooming (Panel A) and the duration of grooming (Panel B) in SIG in mice Vehicle; 2% Tween 20 in Normal saline (10 mL/kg, p.o.), Hal; Haloperidol (1 mg/kg, i.p.), SIG; swim induced grooming, EME, HF, EAF, BF and AF represent ethanol leaf extract, hexane, ethyl acetate, butanol and aqueous fractions of Milicia excelsa respectively. Each bar represents Mean ± SEM, ANOVA; one way analysis of variance followed by Student-Newman Keuls Test, n=6, *P < 0.05 compared to the vehicle treated group

Fig. 2. Antipsychotic effect of EME, HF, EAF, BF and AF on apomorphine-induced climbing test Vehicle; 2% Tween 20 in Normal saline (10 mL/kg, p.o.), Hal; haloperidol (2 mg/kg, i.p.), APO; apomorphine (1.5 mg/kg, s.c.), EME, HF, EAF, BF and AF represent ethanol leaf extract, hexane, ethyl acetate, butanol and aqueous fractions of Milicia excelsa respectively. Each bar represents Mean ± SEM, Kruskal-Wallis followed by Dunn test, n=6, *P < 0.05 compared to the vehicle treated control

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PANEL A

PANEL B

Fig. 3. Antipsychotic effect of EME, HF, EAF, BF and AF on frequency of locomotion (Panel A) and number of ataxia (Panel B) in Ketamine-induced hyperlocomotion test in mice Vehicle; 2% Tween 20 in Normal saline (10 mL/kg, p.o.), Ket; ketamine (10 mg/kg, i.p.), Hal; haloperidol (2 mg/kg, i.p.), EME, HF, EAF, BF and AF ethanol leaf extract, hexane, ethyl acetate, butanol and aqueous fractions of Milicia excelsa respectively. Each bar represents Mean ± SEM, ANOVA; one way analysis of variance followed by Student-Newman Keuls Test, n=6, *P < 0.05 compared to the vehicle treated group

In SIG, EME, EAF, and AF reduced the number effect as well. Of all the fractions in swim-induced of grooming and duration of grooming. Swim- grooming, AF produced the most potent induced grooming is one of the widely used antipsychotic effect. models for screening antipsychotic drugs which are mediated through dopamine D1 receptor EME and EAF inhibited AIC behaviour which is blocking actions [26]. This finding suggests suggestive of D1 and D2 action. Numerous that they may possess antipsychotic effect reports have shown that the ability of substances which is probably mediated via dopamine D1 to antagonize apomorphine-induced climbing receptor blocking action. A number of reports behaviour have been correlated with their have shown that agents that reduced grooming neuroleptic potentials which are mediated via the elicited by immersion in water of mice activation of both D1 and D2 receptors [31]. For showed antipsychotic effects [26]. A previous example, some researchers reported that study [30] showed that reduction in Swim- Securinega virosa extract inhibited the climbing induced grooming behaviour inferred that there elicited by apomorphine in apomorphine-induced was an antipsychotic effect. Thus, the result climbing behaviour in mice [31]. Likewise, others obtained from this study showed that the plant observed reduction in apomorphine-induced extract and fractions reduced grooming climbing test following the administration of behaviour and it could, therefore, be inferred that Morinda citrifolia in mice [5], thus, they both EME, EAF, and AF possessed antipsychotic suggested that these extracts may have

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antipsychotic effects, the mechanism of which treatment of mental and other disorders in involved antagonism of D1 and D2 receptors. Africa/Nigeria [44,45]. For example, Rauwolfia Since, EME and EAF inhibited apomorphine- vomitoria has been used in Nigeria to manage induced climbing behaviour, it could therefore be psychiatric disorders despite orthodox medicine suggested as well that they have antipsychotic [46]. Therefore, conducting scientific findings into effects mediated via the same mechanism. the efficacy and safety of medicinal plants is pertinent and imperative. Moreso, that World EME, HF, EAF, BF, and AF reduced the Health Organisation encourages the incorpora- hyperlocomotion induced by ketamine in KIH at tion of valuable elements of traditional medicine varying degrees. The potency of EME and AF is into national health care systems [47]. This comparable to that of haloperidol (a standard study, therefore, is worthwhile because of the neuroleptic drug). These findings suggest that widespread belief that “green medicine” is EME and the various fractions may have varying cheap, safe, more dependable and degrees of antipsychotic actions that could accessible than the costly synthetic drugs many probably be mediated via dopaminergic neuro- of which are associated with intolerable effects transmission [32]. This is in tune with earlier [48,49]. finding [27]. 5. CONCLUSION A competitive antagonist of NMDA receptor such as ketamine has been shown to induce This study concludes that M. excelsa leaf extract behavioural effects that mimic positive, negative and fractions may have biologically active and cognitive schizophrenic symptoms in healthy antipsychotic principles. The magnitude of humans [33,34,35] as well as behavioural potency of the fractions may be of the order EAF activation in experimental animals [36]. > AF > HF > BF. Thus, lend pharmacological Neuroleptics, such as haloperidol and credence to the suggested ethnomedicinal uses risperidone have been reported to decrease of the leaf in treating insanity in traditional locomotor activity due to the acute depressant medicines. However, further studies may be effect of this class of drugs [37]. This hypomotility warranted to investigate the effect of EME and its caused by neuroleptics may be as a result of fractions on drug-induced catalepsy and ptosis in reduced central nervous system excitability or mice. through sedative effect [37]. A number of research findings have shown the ability of some CONSENT agents to reduce hypermotility induced by ketamine [27,37,38]. For example, the It is not applicable. antipsychotic effect of Alpinia zerumbet has been ascribed to its hypomotility effect in ketamine- ETHICAL APPROVAL induced hyperlocomotion in mice [39]. EME, EAF, and AF reduced ataxia induced by All authors hereby declare that "Principles of ketamine suggesting that the antipsychotic effect laboratory animal care" (NIH publication No. 85- of these substances may also involve 23, revised 1985) were followed, as well as amelioration of glutaminergic neurotransmission specific national laws where applicable. All as dysfunction of glutaminergic neuro- experiments have been examined and approved transmission mediated via the NMDA receptor by the appropriate ethics committee. has been implicated in the pathophysiology of the psychotic illness such as schizophrenia COMPETING INTERESTS [40,41]. AF produced stronger ataxia reducing effect compared to haloperidol, a reference antipsychotic drug. Authors have declared that no competing interests exist. Although the antipsychotic activity elicited by EME, EAF, and AF is less comparable to REFERENCES haloperidol in this study, but the use of medicinal plants in treating diseases has been an integral 1. American Psychiatric Association. part of every culture [42] and a major part of Diagnostic criteria from DSM-IV-TR. Africa heritage [43]. Despite advances in and Washington, DC, USA. 2000;105–209. availability of orthodox medicine, there is still a 2. Abi-Dargham A, Gil R, Krystal J, Ronald M, high patronage of traditional/herbal medicine for Baldwin RM, Seibyl JP, et al. Increased

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